Foamable composition combining a polar solvent and a hydrophobic carrier

ABSTRACT

The present invention relates to a foamable vehicle or cosmetic or pharmaceutical composition, comprising: (1) an organic carrier, at a concentration of 10% to 70% by weight, wherein said organic carrier concurrently comprises: (i) at least one hydrophobic organic carrier, and (ii) at least one polar solvent; (2) at least one surface-active agent; (3) water; and (4) at least one liquefied or compressed gas propellant at a concentration of 3% to 25% by weight of the total composition. 
     The present invention further provides a method of treating, alleviating or preventing a disorder of mammalian subject, comprising administering the above-mentioned compositions to an afflicted target site.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §120 of U.S. patentapplication Ser. No. 11/488,989, filed on Jul. 19, 2006, entitled“Foamable Composition Combining a Polar Solvent and a HydrophobicCarrier”, which claims benefit of priority under 35 U.S.C. §119(e) ofU.S. Provisional Patent Application No. 60/700,702, filed on Jul. 19,2005, entitled “Foamable Composition Combining a Polar Solvent and aHydrophobic Carrier,” both of which are herein incorporated by referencein their entirety.

This application is a continuation-in-part application of co-pendingU.S. application Ser. No. 11/124,676, filed on May 9, 2005, entitled“Vasoactive Kit and Compositions and Uses Thereof,” which is acontinuation-in-part application of co-pending International PatentApplication No. 1603/005527, designating the United States and filed onOct. 24, 2003, which claims the benefit of priority under 35 U.S.C.§119(e) to U.S. Patent Application Ser. No. 60/429,546, filed on Nov.29, 2002, both entitled “Cosmetic and Pharmaceutical Foam,” and whichclaims the benefit of priority under 35 USC§119(a) to Israeli PatentApplication No. 152486, filed Oct. 25, 2002, all of which are herebyincorporated in their entirety by reference.

This application is also a continuation-in-part application ofco-pending U.S. patent application Ser. No. 10/911,367, filed on Aug. 4,2004, which claims the benefit of priority under 35 U.S.C. §119(e) toU.S. Patent Application Ser. No. 60/492,385, filed on Aug. 4, 2003, bothentitled “Foam Carrier Containing Amphiphilic Copolymer Gelling Agent”and both hereby incorporated in their entirety by reference.

This application is also a continuation-in-part application ofco-pending U.S. patent application Ser. No. 10/835,505, filed on Apr.28, 2004, which claims the benefit of priority under 35 U.S.C. §119(e)to U.S. Patent Application Ser. No. 60/530,015, filed on Dec. 16, 2003,and U.S. Patent Application Ser. No. 60/492,385, filed on Aug. 4, 2003,all entitled “Oleaginous Pharmaceutical and Cosmetic Foam” and allhereby incorporated in their entirety by reference.

This application is also a continuation-in-part application ofco-pending U.S. patent application Ser. No. 10/922,358, filed Aug. 20,2004, entitled “Penetrating Pharmaceutical Foam,” which claims thebenefit of priority under 35 U.S.C. §119(e) to U.S. Patent ApplicationSer. No. 60/497,648, filed on Aug. 25, 2003, both of which areincorporated by reference.

BACKGROUND OF THE INVENTION

This invention relates to foamable pharmaceutical and cosmeticcompositions.

Foams and, in particular, foam emulsions are complicated systems whichdo not form under all circumstances. Changes in foam emulsioncomposition, such as by the addition of active ingredients maydestabilize the foam. There is therefore a need for a foam compositionwhich provides desirable properties to the skin and can remain stablewhilst accommodating a variety of active ingredients.

U.S. Pat. No. 6,126,920 (“the '920 Patent”) discloses treatment ofvarious skin diseases, and in particular, scalp psoriasis, using afoamable pharmaceutical composition containing a corticosteroid activesubstance, an aliphatic alcohol, water, a fatty alcohol, asurface-active agent, a propellant and a buffering agent. The foamablecomposition contains 40-90% w/w composition of an aliphatic alcohol. The'920 Patent is typical of many compositions that use aliphatic alcoholsin the foam composition. The alcohol promotes fast drying and therebyattempts to address the sticky feeling left by many topical formulationsafter application; however, alcohols, and in particular the methyl,ethyl and isopropyl alcohols preferred in the '920 Patent, are defattingagents and may cause skin to become dry and cracked. U.S. Pat.Application Pub. No. US2004/0151671 provides pharmaceutical compositionsin a pressurized container, comprising a quick breaking alcoholicfoaming agent. U.S. Pat. No. 5,783,202 provides a pediculicidal moussecomposition containing a pediculicidal agent containing (a) from about0.1 to about 10% w/w of a pediculicidal agent (b) about 70 to about 97%w/w of a foaming agent, which is preferably a quick breaking alcoholicfoaming agent; and (c) from about 3 to about 20% w/w of an aerosolpropellant. U.S. Pat. No. 6,730,288 teaches a pharmaceutical foamcomposition including (a) an active ingredient; (b) an occlusive agent;(c) an aqueous solvent; and (d) an organic cosolvent; wherein the activeingredient is insoluble in water and insoluble in both water and theocclusive agent; and wherein there is enough occlusive agent to form anocclusive layer on the skin.

A few dermatological foam products are available on the market.

OIux™ Foam, produced by Connetics, Inc., contains clobetasol propionate.Each gram of OIux™ Foam contains 0.5 mg clobetasol propionate, USP, in athermolabile foam, which consists of ethanol (60%), purified water,propylene glycol, cetyl alcohol, stearyl alcohol, polysorbate 60, citricacid, and potassium citrate. It is dispensed from an aluminum canpressurized with a hydrocarbon propellant (propane/butane). Luxiq™corticostroid foam medication contains 1.2 mg betamethasone valerate pergram, in a vehicle, comprising ethanol (60.4%), purified water,propylene glycol, cetyl alcohol, stearyl alcohol, polysorbate 60, citricacid, and potassium citrate, and pressurized with a hydrocarbonpropellant. Alcohol is known to impair the integrity of the skinbarrier, dry the skin and cause skin irritation. The incidence skinirritation (burning, itching and stinging) as detailed the packageinserts of the above mentioned products is very high (54%), probably dueto the high alcohol content. Moreover, the respective incidence of skinirritation caused by the vehicle of these foams is 75%.

Thus, while alcohol is useful in solubilizing an active agent andenabling effective dermal penetration of an active agent is desirable,the development of a safe foam vehicle, which will overcome the evidentskin drying and irritation caused by alcohol, is warranted.

Furthermore, foam compositions that possess a lesser degree of thermalsensitivity, thus being more useful for the treatment of large skinareas are desired.

SUMMARY OF THE INVENTION

The present invention relates to a foamable vehicle or cosmetic orpharmaceutical composition comprising:

(1) an organic carrier, at a concentration of about 10% to about 70% byweight, wherein said organic carrier concurrently comprises:

(i) at least one hydrophobic organic carrier and

(ii) at least one polar solvent

(2) at least one surface-active agent;(3) water; and(4) at least one liquefied or compressed gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition.

The present invention further relates to said composition comprising anactive agent.

In some embodiments, the foamable cosmetic or pharmaceutical compositionis non-flammable, wherein said gas propellant containshydrofluorocarbon.

The present invention further provides a method of treating, alleviatingor preventing a disorder of mammalian subject, comprising administeringa therapeutically effective amount of the above-mentioned compositionsto an afflicted target site.

The present invention further provides use of a therapeuticallyeffective amount of the above-mentioned compositions in the manufactureof a medicament.

The present invention further provides a therapeutically effectiveamount of the above-mentioned compositions for use in the manufacture ofa medicament.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a safe and effective foamable cosmetic orpharmaceutical vehicle or composition. The vehicle or compositioncontains a polar solvent, which can optionally be a short-chain alcohol,which possesses (as such) skin drying and skin irritation properties;however, the composition also contains a hydrophobic carrier, whichcounteracts these undesirable effects and overcomes these drawbacks.

In one or more embodiments, the foamable cosmetic or pharmaceuticalvehicle includes:

(1) an organic carrier, at a concentration of about 10% to about 70% byweight, wherein said organic carrier concurrently comprises:

(i) at least one hydrophobic organic carrier and

(ii) at least one polar solvent

(2) at least one surface-active agent;(3) water; and(4) at least one liquefied or compressed gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition.

In one or more embodiments the foamable cosmetic or pharmaceuticalvehicle includes:

(1) an organic carrier, at a concentration of about 10% to about 70% byweight, wherein said organic carrier concurrently comprises

(i) at least one hydrophobic organic carrier, and

(ii) at least one polar solvent;

(2) about 0.1% to about 5% by weight of at least one surface-activeagent;

(3) Water; and

(4) at least one liquefied or compressed gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition.

In one or more embodiments a foamable cosmetic or pharmaceutical vehicleis provided wherein the ratio of the hydrophobic organic carrier and thepolar solvent are selected to provide a selected pharmacological orsafety property;

In one or more embodiments a foamable cosmetic or pharmaceutical vehicleis provided also incorporating a polymeric agent.

In one or more embodiments the polymeric agent is selected from abioadhesive agent, a gelling agent, a film forming agent and a phasechange agent and can be from about 0.01% to about 5% by weight

In one or more embodiments, a pharmaceutical or cosmetic foamableproduct is provided, wherein a pharmaceutical or a cosmetic active agentis incorporated in a foamable vehicle, which contains a polar solventand a hydrophobic organic carrier.

Thus, in one or more embodiments, the pharmaceutical or cosmeticfoamable product comprises:

(1) an effective concentration of at least one pharmaceutical orcosmetic active agent;(2) an organic carrier, at a concentration of about 10% to about 70% byweight, wherein said organic carrier concurrently comprises

(i) at least one hydrophobic organic carrier

(ii) at least one polar solvent;

(3) about 0.1% to about 5% by weight of at least one surface-activeagent; and(4) at least one liquefied or compressed gas propellant at aconcentration of about 3% to about 25% by weight of the totalcomposition.

In one or more embodiments of the pharmaceutical or cosmetic foamableproduct is non-flammable.

Water and optional ingredients are added to complete the total mass to100%.

All % values are provided on a weight (w/w) basis.

Polar Solvent

A “polar solvent” is an organic solvent, typically soluble in both waterand oil. Certain polar solvents posess the beneficial property of aheumectant, being a substance, which helps retain moisture, for examplepropylene glycol and glycerin.

In one or more embodiments, the polar solvent is a heumectant.

According to one or more embodiments, the polar solvent comprises ashort chain alcohol. Short chain alcohols, having up to 5 carbon atomsin their carbon chain skeleton and one hydroxyl group, such as ethanol,propanol, isopropanol, butanol, iso-butanol, t-butanol and pentanol. Inone or more embodiments the concentration of the short chain alcohols isfrom about 5% to about 70%, preferably from about 10% to about 60%.

In one or more embodiments, the polar solvent is a polyol. Polyols areorganic substances that contain at least two hydroxy groups in theirmolecular structure.

In one or more embodiments, the polar solvent contains an diol (acompound that contains two hydroxy groups in its molecular structure),such as propylene glycol (e.g., 1,2-propylene glycol and 1,3-propyleneglycol), butanediol (e.g., 1,4-butanediol), butanediol (e.g.,1,3-butanediol and 1,4-butenediol), butynediol, pentanediol (e.g.,1,5-pentanediol), hexanediol (e.g., 1,6-hexanediol), octanediol (e.g.,1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol, diethyleneglycol, triethylene glycol, tetraethylene glycol, dipropylene glycol anddibutylene glycol.

In one or more embodiments, the polar solvent contains a triol (acompound that contains three hydroxy groups in its molecular structure),such as glycerin and 1,2,6-Hexanetriol.

Other non-limiting examples of polar solvents include pyrrolidones,(such as N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone), dimethylisosorbide, 1,2,6-hexapetriol, dimethyl sulfoxide (DMSO), ethylproxitol, dimethylacetamide (DMAc) and alpha hydroxy acids, such aslactic acid and glycolic acid.

According to still other embodiments, the polar solvent is apolyethylene glycol (PEG) or PEG derivative that is liquid at ambienttemperature, including PEG200 (MW (molecular weight) about 190-210 kD),PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MWabout 570-630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG10000 and mixtures thereof.

Polar solvents are known to enhance the penetration of active agent intothe skin and through the skin, and therefore, their inclusion in thecomposition of the present invention is desirable, despite theirundesirable skin drying and irritation potential. There is at one levela commonality between the different polar solvents and their penetrationenhancement properties. However, lower molecular weight alcohols cansometimes be more potent as a solvent, for example by extracting lipidsfrom the skin layers more effectively, which characteristic canadversely affect the skin structure and cause dryness and irritation.Therefore the selection of the hydrophobic carrier to counteract thesenegative effects may be of more importance when using the lowermoleculular weight alcohols.

Hydrophobic Solvent

A “hydrophobic organic carrier” as used herein refers to a materialhaving solubility in distilled water at ambient temperature of less thanabout 1 gm per 100 mL, more preferable less than about 0.5 gm per 100mL, and most preferably less than about 0.1 gm per 100 mL.

The identification of a hydrophobic organic carrier or “hydrophobicsolvent”, as used throughout this specification synonymously, is notintended to characterize the solubilization capabilities of the solventfor any specific active agent or any other component of the foamablecomposition. Rather, such information is provided to aid in theidentification of materials suitable for use as a hydrophobic carrier inthe foamable compositions described herein.

In one or more embodiments, the hydrophobic organic carrier is ahigh-melting point hydrocarbon, such as, petrolatum.

In one or more other embodiments the use of high melting pointhydrocarbons, such as petrolatum in concentrations of more than 10%, arenot desirable since they have a waxy feeling when applied to the skin;yet, in certain additional embodiments, when an extensive refattingeffect is required, then petrolatum in concentrations of more than 10%,for example between about 10% and about 50% is included in thecomposition of the present invention.

According to one or more embodiments, hydrophobic solvents are liquidoils originating from vegetable, marine or animal sources. Suitableliquid oil includes saturated, unsaturated or polyunsaturated oils. Byway of example, the unsaturated oil may be olive oil, corn oil, soybeanoil, canola oil, cottonseed oil, coconut oil, sesame oil, sunflower oil,borage seed oil, syzigium aromaticum oil, hempseed oil, herring oil,cod-liver oil, salmon oil, flaxseed oil, wheat germ oil, eveningprimrose oils or mixtures thereof, in any proportion.

Suitable hydrophobic solvents also include polyunsaturated oilscontaining poly-unsaturated fatty acids. In one or more embodiments, theunsaturated fatty acids are selected from the group of omega-3 andomega-6 fatty acids. Examples of such polyunsaturated fatty acids arelinoleic and linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoicacid (EPA) and docosahexaenoic acid (DHA). Such unsaturated fatty acidsare known for their skin-conditioning effect, which contribute to thetherapeutic benefit of the present foamable composition. Thus, thehydrophobic solvent can include at least 6% of an oil selected fromomega-3 oil, omega-6 oil, and mixtures thereof.

In the context of the present invention, oils that possesstherapeutically beneficial properties are termed as “therapeuticallyactive oil.”

Another class of hydrophobic solvents is the essential oils, which arealso considered therapeutically active oils, and which contain activebiologically occurring molecules and, upon topical application, exert atherapeutic effect. Non-limiting examples of essential oils includerosehip oil, which contain retinoids and is known to reduce acne andpost-acne scars, and tea tree oil, which possess antibacterial,antifungal and antiviral properties. Other examples of essential oilsare oils of anise, basil, bergemont, camphor, cardamom, carrot, canola,cassia, catnip, cedarwood, citronella, clove, cypress, eucalyptus,frankincense, garlic, ginger, grapefruit, hyssop, jasmine, jojova,lavender, lavandin, lemon, lime, mandarin, marjoram, myrrh, neroli,nutmeg, orange, peppermint, petitgrain, rosemary, sage, spearmint, staranise, tangerine, thyme vanilla, verbena and white clover.

Another class of therapeutically active oils includes liquid hydrophobicplant-derived oils, which are known to possess therapeutic benefits whenapplied topically.

Silicone oils also may be used and are desirable due to their known skinprotective and occlusive properties. Suitable silicone oils includenon-volatile silicones, such as polyalkyl siloxanes, polyaryl siloxanes,polyalkylaryl siloxanes and polyether siloxane copolymers,polydimethylsiloxanes (dimethicones) andpoly(dimethylsiloxane)-(diphenyl-siloxane) copolymers. Silicone oils arealso considered therapeutically active oil, due to their barrierretaining and protective properties.

A further class of hydrophobic carriers includes hydrophobic liquids,selected from the family of organic liquids described as “emollients.”Emollients possess a softening or soothing effect, especially whenapplied to body areas, such as the skin and mucosal surfaces. Examplesof suitable emollients include isopropyl myristate, isopropyl palmitate,isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate,maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate,tocopheryl acetate, cetyl acetate, tocopheryl linoleate, wheat germglycerides, arachidyl propionate, myristyl lactate, decyl oleate,propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityltetrastearate, neopentylglycol dicaprylate/dicaprate, isononylisononanoate, isotridecyl isononanoate, myristyl myristate, octyldodecanol, sucrose esters of fatty acids and octyl hydroxystearate.

The foamable composition of the present invention can be an emulsion, ormicroemulsion, including an aqueous phase and an organic carrier phase.

One non-limiting benefit of combining a polar solvent and a hydrophobiccarrier is apparent in the resulting conservation of skin barrierproperties.

Another non-limiting benefit of combining a polar solvent and ahydrophobic carrier is further apparent in the reduction of skinirritation.

Another non-limiting benefit of the vehicle or composition of thepresent invention is to provide increased penetration of the active orbeneficial agent whilst replenishing the skin for example bymoisturizing or adding fats or oils.

The ratio between the polar solvent and the hydrophobic carrier isdetermined according to the desirable pharmacologic and safetyproperties of the product. Typically, the polar solvent to hydrophobiccarrier ranges between about 1:4 and about 4:1, for example, about 1:4,about 1:2, about 3:4, about 1:1, about 5:4, about 4:2, about 2:1, about3:1 and about 4:1. When high solubilization and/or enhanced dermal ortransdermal delivery of a drug is desirable, the polar solvent tohydrophobic carrier is selected within the range of about 1:1 and about4:1, for example, about 1:1, about 5:4. about 6:4, about 7:4, about 2:1,about 3:1 and about 4:1 Yet, in other case, when the need of enhancedskin protection and skin barrier build-up is more pronounced, the polarsolvent to hydrophobic carrier is selected within the range of about 2:8and about 1:1, for example, about 1:4, about 1:2, about 3:4 and about1:1.

The following table, Table 1 exemplifies, in a non-limiting manner,pairs of polar solvent and the hydrophobic carrier, as provided in thepresent invention. The examples of the previous paragraph areincorporated herin by reference.

Exemplary Polar Solvent/ Exemplary Polar Hydrophobic Hydrophobic SolventCarrier Carrier Ratio Comment A short chain A hydrophobic Between aboutTo provide enhanced alcohol, selected carrier, selected 1:4 and aboutdelivery of an active from ethanol, from mineral oil, 4:1. agent, whileconserving propanol, petrolatum, isopropyl skin barrier isopropanol,myristate, isopropyl To provide enhanced butanol palmytate, a skinbarrier build-up, triglyceride and which facilitates the silicone oilrecovery of damaged skin. A short chain Ester of fatty acid Betweenabout To provide enhanced alcohol, selected 1:4 and about delivery of anactive from ethanol, 4:1. agent, while conserving propanol, skin barrierisopropanol, To provide enhanced butanol skin barrier build-up, whichfacilitates the recovery of damaged skin. A short chain Combination ofat Between about To provide enhanced alcohol, selected least onetriglyceride 1:4 and about delivery of an active from ethanol, and atleast one 4:1. agent, while conserving propanol, ester of a fatty acidskin barrier isopropanol, To provide enhanced butanol skin barrierbuild-up, which facilitates the recovery of damaged skin. A polyethyleneA hydrophobic Between about To provide enhanced glycol PEG carrier,selected 1:1 and about delivery of an active from mineral oil, 4:1agent, while conserving petrolatum, isopropyl skin barrier myristate,isopropyl palmytate, a triglyceride and silicone oil Dimethyl Ahydrophobic Between about To provide enhanced isosorbide carrier,selected 1:1 and about delivery of an active from mineral oil, 4:1agent, while conserving petrolatum, isopropyl skin barrier myristate,isopropyl To provide enhanced palmytate, a skin barrier build-up,triglyceride and which facilitates the silicone oil recovery of damagedskin. Dimethyl A triglyceride Between about To provide increasedisosorbide 4:1 and about solubility of a drug, 1:4, enhanced deliveryand skin barrier build-up Dimethyl Capric-caprylic Between about Toprovide increased isosorbide triglyceride 1:4 and about solubility of adrug, 1:1 enhanced delivery and skin barrier build-up Dimethyl Ester offatty acid Between about To provide increased isosorbide 1:4 and aboutsolubility of a drug, 1:1 enhanced delivery and skin barrier build-upDimethyl Combination of at Between about To provide increased isosorbideleast one triglyceride 1:4 and about solubility of a drug, and at leastone 1:1 enhanced delivery and ester of a fatty acid skin barrierbuild-up A diol selected A hydrophobic Between about To provide enhancedfrom the group of carrier, selected 4:1 and about skin barrier build-uppropylene glycol, from mineral oil, 1:4 butanediol, petrolatum,isopropyl hexanediol, myristate, isopropyl octanediol, palmytate, apropanediol, triglyceride and diethylene glycol, silicone oiltriethylene glycol, tetraethylene glycol, dipropylene glycol anddibutylene glycol. A triol (a A hydrophobic Between about To provideenhanced compound that carrier, selected 4:1 and about skin barrierbuild-up contains three from mineral oil, 1:4 hydroxy groups inpetrolatum, isopropyl its molecular myristate, isopropyl structure),such as palmytate, a glycerin and 1,2,6- triglyceride Hexanetriol. Analpha hydroxy A hydrophobic Between about To provide enhanced acids,such as carrier, selected 4:1 and about skin barrier build-up lacticacid and from mineral oil, 1:4 glycolic acid petrolatum, isopropylmyristate, isopropyl palmytate, a triglyceride DMSO A hydrophobicBetween about To provide enhanced carrier, selected 4:1 and about skinbarrier build-up from mineral oil, 1:4, petrolatum, isopropyl myristate,isopropyl palmytate, a triglyceride A pyrrolidone, A hydrophobic Betweenabout To provide enhanced such as N-methyl- carrier, selected 4:1 andabout skin barrier build-up 2-pyrrolidone and from mineral oil, 1:41-methyl-2- petrolatum, isopropyl pyrrolidinone myristate, isopropylpalmytate, a triglyceride A combination of A hydrophobic Between aboutTo provide enhanced at least two polar carrier, selected 1:4 and aboutdelivery of an active solvents from mineral oil, 4:1. agent, whileconserving petrolatum, isopropyl skin barrier myristate, isopropyl Toprovide enhanced palmytate, a skin barrier build-up, triglyceride andwhich facilitates the silicone oil recovery of damaged skin. Acombination of Ester of fatty acid Between about To provide increased atleast two polar 1:4 and about solubility of a drug, solvents 1:1enhanced delivery and skin barrier build-up A combination of Combinationof at Between about To provide increased at least two polar least onetriglyceride 1:4 and about solubility of a drug, solvents and at leastone 1:1 enhanced delivery and ester of a fatty acid skin barrierbuild-up

In one or more embodiments, the polar solvent consists of a single polarsolvent. Yet, in additional embodiments, the polar solvent consists of acombination of two or more polar solvents.

In one or more embodiments, the hydrophobic carrier consists of a singlepolar solvent. Yet, in additional embodiments, the hydrophobic carrierconsists of a combination of two or more hydrophobic carriers.

In order to derive a composition which is readily foamable upon releasefrom a pressurized container, additional components are required, asprovided hereinbelow.

Surface Active Agent

Surface-active agents (also termed “surfactants”) include any agentlinking oil and water in the composition, in the form of emulsion. Asurfactant's hydrophilic/lipophilic balance (HLB) describes theemulsifier's affinity toward water or oil. The HLB scale ranges from 1(totally lipophilic) to 20 (totally hydrophilic), with 10 representingan equal balance of both characteristics. Lipophilic emulsifiers formwater-in-oil (w/o) emulsions; hydrophilic surfactants form oil-in-water(o/w) emulsions. The HLB of a blend of two emulsifiers equals the weightfraction of emulsifier A times its HLB value plus the weight fraction ofemulsifier B times its HLB value (weighted average). The surface-activeagent according to the present invention has an HLB value, suitable forstabilizing an emulsion comprising the aqueous phase and the organiccarrier of the composition.

According to one or more embodiments of the present invention, thesurface-active agent has a hydrophilic lipophilic balance (HLB) betweenabout 9 and about 14, which is the required HLB (the HLB required tostabilize an O/W emulsion of a given oil) of most oils and hydrophobicsolvents. Thus, in one or more embodiments, the composition contains asingle surface active agent having an HLB value between about 9 andabout 14 (e.g., about 9, about 10, about 11, about 12, about 13 andabout 14), and in one or more embodiments, the composition contains morethan one surface active agent and the weighted average of their HLBvalues is between about 9 and about 14 (e.g. about 9, about 10, about11, about 12, about 13 and about 14). Yet, in other embodiments, when awater-in-oil emulsion is desirable, the composition contains one or moresurface-active agents, having an HLB value between about 2 and about 9(e.g., about 2, about 3, about 4, about 5, about 6, about 7, about 8 andabout 9).

The surface-active agent is selected from anionic, cationic, nonionic,zwitterionic, amphoteric and ampholytic surfactants, as well as mixturesof these surfactants. Such surfactants are well known to those skilledin the therapeutic and cosmetic formulation art. Non-limiting examplesof possible surfactants include polysorbates, such as polyoxyethylene(20) sorbitan monostearate (Tween 60) and poly(oxyethylene) (20)sorbitan monooleate (Tween 80); poly(oxyethylene) (POE) fatty acidesters, such as Myrj 45, Myrj 49, Myrj 52 and Myrj 59; poly(oxyethylene)alkylyl ethers, such as poly(oxyethylene) cetyl ether, poly(oxyethylene)palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycolcetyl ether, brij 38, brij 52, brij 56 and brij W1; sucrose esters,partial esters of sorbitol and its anhydrides, such as sorbitanmonolaurate and sorbitan monolaurate; mono or diglycerides,isoceteth-20, sodium methyl cocoyl taurate, sodium methyl oleoyltaurate, sodium lauryl sulfate, triethanolamine lauryl sulfate andbetaines.

In one or more embodiments of the present invention, the surface-activeagent includes a non-ionic surfactant. Ionic surfactants are known to beirritants. Therefore, non-ionic surfactants are preferred inapplications including sensitive tissue such as found in most mucosaltissues, especially when they are infected or inflamed. We havesurprisingly found that non-ionic surfactants alone provide foams ofexcellent quality, i.e. a score of “E” according to the grading scalediscussed herein below.

In one or more embodiments, the surface-active agent includes a mixtureof a non-ionic surfactant and an ionic surfactant in a ratio in therange of about 100:1 to about 6:1. In one or more embodiments, thenon-ionic to ionic surfactant ratio is greater than about 6:1, orgreater than about 8:1; or greater than about 14:1, or greater thanabout 16:1, or greater than about 20:1.

In one or more embodiments of the present invention, a combination of anon-ionic surfactant and an ionic surfactant (such as sodium laurylsulphate and cocamidopropylbetaine) is employed, at a ratio of between1:1 and 20:1, for example, about 1:1, about 4:1, about 8:1, about 12:1,about 16:1 and about 20:1 or at a ratio of 4:1 to 10:1, for example,about 4:1, about 6:1, about 8:1 and about 10:1. The resultant foam has alow specific gravity, e.g., less than 0.1 g/ml.

Thus, in an exemplary embodiment, a combination of an non-ionicsurfactant having HLB of less than about 9 and an non-ionic surfactanthaving HLB of equal or more than about 9 is employed, at a ratio ofbetween about 1:8 and about 8:1, or at a ratio of about 4:1 to about1:4, wherein the HLB of the combination of emulsifiers is between about9 and about 14.

In one or more embodiments of the present invention, the surface-activeagent includes mono-, di- and tri-esters of sucrose with fatty acids(sucrose esters), prepared from sucrose and esters of fatty acids or byextraction from sucro-glycerides. Suitable sucrose esters include thosehaving high monoester content, which have higher HLB values.

The total surface-active agent is in the range of about 0.1 to about 5%of the composition, and is occasionally less than about 2% or less thanabout 1%.

Polymeric Agent

In one or more embodiments, the foamable composition contains apolymeric agent. The polymeric agent serves to stabilize the foamcomposition and to control drug residence in the target organ. Exemplarypolymeric agents are classified below in a non-limiting manner. Incertain cases, a given polymer can belong to more than one of theclasses provided below.

In one or more embodiments, the composition of the present inventionincludes a gelling agent. A gelling agent controls the residence of atherapeutic composition in the target site of treatment by increasingthe viscosity of the composition, thereby limiting the rate of itsclearance from the site. Many gelling agents are known in the art topossess mucoadhesive properties.

The gelling agent can be a natural gelling agent, a synthetic gellingagent and an inorganic gelling agent. Exemplary gelling agents that canbe used in accordance with one or more embodiments of the presentinvention include, for example, naturally-occurring polymeric materials,such as locust bean gum, sodium alginate, sodium caseinate, egg albumin,gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seedextract, tragacanth gum, guar gum, starch, chemically modified starchesand the like, semi-synthetic polymeric materials such as celluloseethers (e.g. hydroxyethyl cellulose, hydroxypropyl cellulose, methylcellulose, carboxymethyl cellulose, methylhydroxyethylcellulose,methylhydroxypropylcellulose, hydroxypropylmethyl cellulose,hydroxyethylcarboxymethylcellulose, carboxymethylcellulose andcarboxymethylhydroxyethylcellulose), guar gum, hydroxypropyl guar gum,soluble starch, cationic celluloses, cationic guars, and the like, andsynthetic polymeric materials, such as carboxyvinyl polymers,polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers,polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinylchloride polymers, polyvinylidene chloride polymers and the like.Mixtures of the above compounds are also contemplated.

Further exemplary gelling agents include the acrylic acid/ethyl acrylatecopolymers and the carboxyvinyl polymers. Non-limiting examples includeCarbopol® 934, Carbopol® 940, Carbopol® 950, Carbopol® 980, Carbopol®951 and Carbopol® 981.

Yet, in other embodiments, the gelling agent includes inorganic gellingagents, such as silicone dioxide (fumed silica).

Mucoadhesive/bioadhesion has been defined as the attachment of syntheticor biological macromolecules to a biological tissue. Mucoadhesive agentsare a class of polymeric biomaterials that exhibit the basiccharacteristic of a hydrogel, i.e. swell by absorbing water andinteracting by means of adhesion with the mucous that covers epithelia.Compositions of the present invention may contain a mucoadhesivemacromolecule or polymer in an amount sufficient to confer bioadhesiveproperties. The bioadhesive macromolecule enhances the delivery ofbiologically active agents on or through the target surface. Themucoadhesive macromolecule may be selected from acidic syntheticpolymers, preferably having an acidic group per four repeating ormonomeric subunit moieties, such as poly(acrylic)- and/orpoly(methacrylic) acid (e.g., Carbopol®, Carbomer®), poly(methylvinylether/maleic anhydride) copolymer, and their mixtures and copolymers;acidic synthetically modified natural polymers, such ascarboxymethylcellulose (CMC); neutral synthetically modified naturalpolymers, such as (hydroxypropyl)methylcellulose; basic amine-bearingpolymers such as chitosan; acidic polymers obtainable from naturalsources, such as alginic acid, hyaluronic acid, pectin, gum tragacanth,and karaya gum; and neutral synthetic polymers, such as polyvinylalcohol or their mixtures. An additional group of mucoadhesive polymersincludes natural and chemically modified cyclodextrin, especiallyhydroxypropyl-β-cyclodextrin. Such polymers may be present as freeacids, bases, or salts, usually in a final concentration of about 0.01%to about 0.5% by weight. Many mucoadhesive agents are known in the artto also possess gelling properties.

In one or more embodiments, the polymeric agent contains a film-formingcomponent. The film-forming component may include a water-insolublealkyl cellulose or hydroxyalkyl cellulose. Exemplary alkyl cellulose orhydroxyalkyl cellulose polymers include ethyl cellulose, propylcellulose, butyl cellulose, cellulose acetate, hydroxypropyl cellulose,hydroxybutyl cellulose, and ethylhydroxyethyl cellulose, alone or incombination. In addition, a plasticizer or a cross-linking agent may beused to modify the polymer's characteristics. For example, esters suchas dibutyl or diethyl phthalate, amides such as diethyldiphenyl urea,vegetable oils, fatty acids and alcohols such as oleic and myristyl acidmay be used in combination with the cellulose derivative.

In one or more embodiments, the polymeric agent includes a phase changepolymer, which alters the composition behavior from fluid-like prior toadministration to solid-like upon contact with the target mucosalsurface. Such phase change results from external stimuli, such aschanges in temperature or pH and exposure to specific ions (e.g., Ca²⁺).Non-limiting examples of phase change polymers includepoly(N-isopropylamide) and Poloxamer 407®.

The polymeric agent is present in an amount in the range of about 0.01%to about 5.0% by weight of the foam composition. In one or moreembodiments, it is typically less than about 1 wt % of the foamablecomposition.

Preferably, a therapeutically effective foam adjuvant is included in thefoamable compositions of the present invention to increase the foamingcapacity of surfactants and/or to stabilize the foam. In one or moreembodiments of the present invention, the foam adjuvant agent includesfatty alcohols having 15 or more carbons in their carbon chain, such ascetyl alcohol and stearyl alcohol (or mixtures thereof). Other examplesof fatty alcohols are arachidyl alcohol (C20), behenyl alcohol (C22),1-triacontanol (C30), as well as alcohols with longer carbon chains (upto C50). Fatty alcohols, derived from beeswax and including a mixture ofalcohols, a majority of which has at least 20 carbon atoms in theircarbon chain, are especially well suited as foam adjuvant agents. Theamount of the fatty alcohol required to support the foam system isinversely related to the length of its carbon chains. Foam adjuvants, asdefined herein are also useful in facilitating improved spreadabilityand absorption of the composition.

In one or more embodiments of the present invention, the foam adjuvantagent includes fatty acids having 16 or more carbons in their carbonchain, such as hexadecanoic acid (C16) stearic acid (C18), arachidicacid (C20), behenic acid (C22), octacosanoic acid (C28), as well asfatty acids with longer carbon chains (up to C50), or mixtures thereof.As for fatty alcohols, the amount of fatty acids required to support thefoam system is inversely related to the length of its carbon chain.

In one or more embodiments, a combination of a fatty acid and a fattyester is employed.

Optionally, the carbon atom chain of the fatty alcohol or the fatty acidmay have a double bond. A further class of foam adjuvant agent includesa branched fatty alcohol or fatty acid. The carbon chain of the fattyacid or fatty alcohol also can be substituted with a hydroxyl group,such as 12-hydroxy stearic acid.

A property of the fatty alcohols and fatty acids used in context of thecomposition of the present invention is related to their therapeuticproperties per se. Long chain saturated and mono unsaturated fattyalcohols, e.g., stearyl alcohol, erucyl alcohol, arachidyl alcohol andbehenyl alcohol (docosanol) have been reported to possess antiviral,antiinfective, antiproliferative and antiinflammatory properties (see,U.S. Pat. No. 4,874,794). Longer chain fatty alcohols, e.g.,tetracosanol, hexacosanol, heptacosanol, octacosanol, triacontanol,etc., are also known for their metabolism modifying properties andtissue energizing properties. Long chain fatty acids have also beenreported to possess anti-infective characteristics.

In one or more embodiments, the active agent is encapsulated inparticles, microparticles, nanoparticles, microcapsules, spheres,microspheres, nanocapsules, nanospheres, liposomes, niosomes, polymermatrix, nanocrystals or microsponges.

The composition of the present invention may further optionally includea variety of formulation excipients, which are added in order tofine-tune the consistency of the formulation, protect the formulationcomponents from degradation and oxidation and modify their consistency.Such excipients may be selected, for example, from stabilizing agents,antioxidants, humectants, preservatives, colorant and odorant agents andother formulation components, used in the art of formulation.

Aerosol propellants are used to generate and administer the foamablecomposition as a foam. The total composition including propellant,foamable compositions and optional ingredients is referred to as thefoamable carrier. The propellant makes up about 3% to about 25% (w/w) ofthe foamable carrier or composition. Examples of suitable propellantsinclude volatile hydrocarbons such as butane, propane, isobutane ormixtures thereof, and fluorocarbon gases.

Non-Flammable Stable Foam Compositions

Alcohol and organic solvents render foams inflammable. It has beensurprisingly discovered that fluorohydrocarbon propellants, other thanchloro-fluoro carbons (CMOs), which are non-ozone-depleting propellants,are particularly useful in the production of a non-flammable foamablecomposition. A test according to European Standard prEN 14851, titled“Aerosol containers—Aerosol foam flammability test” revealed thatcompositions containing an organic carrier that contains a hydrophobicorganic carrier and/or a polar solvent, which are detected asinflammable when a hydrocarbon propellant is used, become non-flammable,while the propellant is an HFC propellant.

Such propellants include, but are not limited to, hydrofluorocarbon(HFC) propellants, which contain no chlorine atoms, and as such, fallcompletely outside concerns about stratospheric ozone destruction bychlorofluorocarbons or other chlorinated hydrocarbons. Exemplarynon-flammable propellants according to this aspect of the inventioninclude propellants made by DuPont under the registered trademark Dymel,such as 1,1,1,2 tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3heptafluoropropane (Dymel 227). HFCs possess Ozone Depletion Potentialof 0.00 and thus, they are allowed for use as propellant in aerosolproducts.

Notably, the stability of foamable emulsions including HFC as thepropellant is improved in comparison with the same composition made witha hydrocarbon propellant.

Active Agents

It is to be understood that the active agents useful herein can in someinstances provide more than one benefit or operate via more than onemode of action. Therefore, classifications herein are made for the sakeof convenience and are not intended to limit the active agent to thatparticular application or applications listed.

The composition of the present invention comprises an active agent thatprovides therapeutic or cosmetic activity.

Non-limiting examples of active agents include an anti-infective, anantibiotic, an antibacterial agent, an antifungal agent, an antiviralagent, an antiparasitic agent, a steroidal anti-inflammatory agent, anonsteroidal anti-inflammatory agent, an immunosuppressive agent, animmunomodulator, an immunoregulating agent, a hormonal agent, a steroid,a vasoactive agent, a vasoconstrictor, a vasodilator, vitamin A, avitamin A derivative, a retinoid, vitamin B, a vitamin B derivative,vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative,vitamin E, a vitamin E derivative, vitamin F, a vitamin F derivative,vitamin K, a vitamin K derivative, a wound healing agent, a burn healingagent, a disinfectant, an anesthetic, an antiallergic agent, an alphahydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, aprotein, a peptide, a neuropeptide, an allergen, an immunogenicsubstance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylicacid, azelaic acid, sebacic acid, adipic acid, fumaric acid, aninsecticide, an antiproliferative agent, an anticancer agent, aphotodynamic therapy agent, an anti-wrinkle agent, a radical scavenger,a metal oxide (e.g., titanium dioxide, zinc oxide, zirconium oxide, ironoxide), silicone oxide, talc, an anti-acne agent, a skin whiteningagent, a self tanning agent, an anti-cellulite agent, a skin protectiveagent, a masking agent, an anti-wart agent, a refatting agent, alubricating agent and mixtures thereof at any proportion. Theconcentration of the active agent can be adapted to exert a therapeuticeffect on a disease when applied to an afflicted area. Various differenttherapeutic effects of the herbs and their extracts are, for example,illustrated in the above-mentioned references.

In one or more embodiments the active agent may be an extract ortincture of one or more beneficial agents that have beneficialproperties, for example, when applied to the skin, a body surface, abody cavity or a mucosal surface. The extract can be, for example,alcoholic, hydroalcoholic, propelyne glycol, glycerine, dry, press,cold, hot, liquid carbon dioxide, oil or other process known in the art.The extract or tincture may comprise of substances of animal, plant,(such as herb, fruit, vegetable) mineral or other origin. Nonlimitingexamples are proteins, polypepeptides, sugars, hyularonic acid, and coaltar. Herbal extracts may be from any known therapeutic herb, as listedfor example in Herbal Medicines, London: Pharmaceutical Press ElectronicVersion 2006 or in the American Herbal Association electronicpublication Herbal gram or in German Commission E., such as, angelica,calendula, celery, coltsfoot, comfrey, dandelion, jamaica dogwood, kava,marshmallow, prickly ash, northern prickly ash, southern senna,valerian, agrimony, aloe vera, alfalfa, artichoke, avens, bayberry,bloodroot, blue flag, bogbean, boldo, boneset, broom, buchu, burdock,burnet, calamus, calendula, cascara, centaury, cereus, chamomile, germanchamomile, roman chamomile, cinnamon, clivers, cohosh, black, cohosh,blue, cola, corn silk, couchgrass, cowslip, damiana, devil's claw,drosera, echinacea, elder, elecampane, euphorbia, eyebright, figwort,frangula, fucus, fumitory, garlic, golden seal, gravel root, ground ivy,guaiacum, hawthorn, holy thistle, hops, horehound black, horehoundwhite, horse chestnut hydrangea, ispaghula, juniper, lady's lipper,liferoot, lime flower, liquorice, lobelia, mate, meadowsweet, mistletoe,motherwort, myrrh, nettle, parsley, parsley piert, passionflower,pennyroyal, pilewort, plantain, pleurisy root, pokeroot, poplar,pulsatilla, queen's delight, raspberry, red clover, rosemary, sage,sarsaparilla, sassafras, scullcap, senega, shepherd's purse, skunkcabbage, slippery elm, squill, St. john's wort, stone root, tansy,thyme, uva-ursi, vervain, wild carrot, wild lettuce, willow, witchhazel, yarrow and yellow dock.

When the extract is dissolved in a polar solvent, such as a short chainalcohol (e.g., ethanol and isopropyl alcohol), propelyne glycol andglycerin, then the polar solvent of the extract can also comprise partor all of the “polar solvent” component of the foamable composition, asspecified throughout this specification and likewise the polar solventof the foamable composition can also comprise as part or all of the“polar solvent” component of the extract.

In one or more embodiments, the active agent is an anti-infective agent,selected from an antibiotic agent, an antibacterial agent, ananti-fungal agent, an anti-viral agent and an anti-parasite agent.

The antibacterial drug can be active against gram positive andgram-negative bacteria, protozoa, aerobic bacteria and unaerobic ones.

In one or more embodiments, the antibiotic agent is selected from theclasses consisting of beta-lactam antibiotics, synthetic andsemi-synthetic penicillins, aminoglycosides, ansa-type antibiotics,anthraquinones, antibiotic azoles, antibiotic glycopeptides, macrolides,antibiotic nucleosides, antibiotic peptides, antibiotic polyenes,antibiotic polyethers, quinolones, fluoroquinolnes, antibiotic steroids,cyclosporines, sulfonamides, tetracycline, chloramphenicol, dicarboxylicacids, such as azelaic acid, salicylates, antibiotic metals, oxidizingagents, substances that release free radicals and/or active oxygen,cationic antimicrobial agents, quaternary ammonium compounds,biguanides, triguanides, bisbiguanides and analogs and polymers thereofand naturally occurring antibiotic compounds.

Additional antibacterial agents, which are non-specific, include strongoxidants and free radical liberating compounds, such as hydrogenperoxide, bleaching agents (e.g., sodium, calcium or magnesiumhypochloride and the like), iodine, chlorohexidine and benzoyl peroxide.

The antifungal agent can be an azole compound. Exemplary azole compoundsinclude azoles selected from the group consisting of azoles, diazoles,triazoles, miconazole, ketoconazole, clotrimazole, econazole,mebendazole, bifonazole, butoconazole, fenticonazole, isoconazole,oxiconazole, sertaconazole, sulconazole, thiabendazole, tiaconazole,fluconazole, itraconazole, ravuconazole and posaconazole.

Additional exemplary antifungal agents include griseofulvin, ciclopirox,amorolfine, terbinafine, Amphotericin B, potassium iodide, flucytosine(5FC) and any combination thereof at a therapeutically effectiveconcentration.

In one or more embodiments, the active agent is an anti-viral agent. Anyknown antiviral agent, in a therapeutically effective concentration, canbe incorporated in the foam composition of the present invention.Exemplary antiviral agents include, but not limited to, acyclovir,famciclovir, gancyclovir, valganciclovir and abacavir.

In another embodiment according to the present invention, the activeagent is an anti-inflammatory or anti-allergic agent. Anti-inflammatoryagents can be selected from the group of corticosteroids, non-steroidalanti-inflammatory drugs (NSAIDs), antihistamines, immunosuppressantagents, immunomodulators; and any combination thereof at atherapeutically effective concentration.

Non-limiting examples of corticosteroids include hydrocortisone,hydrocortisone acetate, desonide, betamethasone valerate,clobetasone-17-butyrate, flucinonide, fluocinolone acetonide,alcometasone dipropionate, mometasone furoate, prednicarbate,triamcinolone acetonide, betamethasone-17-benzoate, methylprednisoloneaceponate, betamethasone dipropionate, halcinonide, triamcinoloneacetonide, halobetasol and clobetasol-17-propionate.

A second class of anti-inflammatory agents, which is useful in the foamof the present invention, includes the nonsteroidal anti-inflammatoryagents (NSAIDs). The variety of compounds encompassed by this group iswell known to those skilled in the art. Specific non-steroidalanti-inflammatory agents useful in the composition invention include,but are not limited to, oxicams, such as piroxicam, isoxicam, tenoxicam,sudoxicam; salicylates, such as salicylic acid, ethyl salicylate, methylsalycilate, aspirin, disalcid, benorylate, trilisate, safapryn, solprin,diflunisal, and fendosal; scetic acid derivatives, such as diclofenac,fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac,tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac,oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic,meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acidderivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen,ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen,oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen,and tiaprofenic; and pyrazoles, such as phenylbutazone, oxyphenbutazone,feprazone, azapropazone, and trimethazone.

Any further steroidal and nonsteroidal compounds, having the capacity toprevent, alleviate the symptoms of, treat or cure inflammationprocesses, are generally included, as possible anti-inflammatory agents,according to the present invention.

Antiallergic active agents include antihistamine compounds, including,in a non limiting manner, thylenediamines, such as pyrilamine(mepyramine), antazoline and methapyrilene; tripelennaminephenothiazines, such as promethazine, methdilazine and trimeprazine;ethanolamines, such as diphenhydramine, bromodiphenhydramine,carbinoxamine, clemastine, dimenhydrinate, diphenylpyraline, doxylamineand phenyltoxamine; piperazines, such as cyclizine, buclizine,chlorcyclizine, hydroxyzine, meclizine and thiethylperazine;alkylamines, such as brompheniramine, pyrrobutamin, desbrompheniramine,tripolidine, dexchlorpherniramine, chlorpheniramine; dimethindene andpheniramine; and piperidines, such as cyproheptadine and azatadine.These active agents, as well as additional antihistamines can also beincorporated in the composition of the present invention.

The composition of the present invention may also comprise ananti-inflammatory or antiallergic agent, wherein said agent reduces theoccurrence of pro-inflammatory cytokines or inhibits the effect ofpro-inflammatory cytokines.

Immunosuppressant agents, immunoregulating agents and immunomodulatorsare chemically or biologically derived agents that modify the immuneresponse or the functioning of the immune system (as by the stimulationof antibody formation or the inhibition of white blood cell activity).Immunosuppressant agents and immunomodulators include, among otheroptions, cyclic peptides, such as cyclosporine, tacrolimus, tresperimus,pimecrolimus, sirolimus (rapamycin), verolimus, laflunimus, laquinimodand imiquimod.

In one or more embodiments, the active agent is a topical anesthetic.Examples of topical anesthetic drugs include, but not limited to,benzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine,etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine,cocaine, ketamine, pramoxine, and phenol. Mixtures of such anestheticagents may be synergistically beneficial.

In one or more embodiments, the active agent is a “keratolyticallyactive agent.” The term “keratolytically active agent” refers herein toa compound which loosens and removes the stratum corneum of the skin, oralters the structure of the keratin layers of the skin.

Suitable keratolytically active agents include phenol and substitutedphenolic compounds. Such compounds are known to dissolve and loosen theintracellular matrix of the hyperkeratinized tissue. Dihydroxy benzeneand derivatives thereof have been recognized as potent keratolyticagents. Resorcinol (m-dihydroxybenzene) and derivatives thereof are usedin anti-acne preparations. Hydroquinone (p-dihydroxybenzene), besidesits anti-pigmentation properties, is also keratolytic.

Vitamin A and its derivatives, such as retinoic acid, isoretinoic acid,retinol and retinal are another preferred class of keratolyticallyactive agents.

Another group of keratolytically active agents include alpha-hydroxyacids, such as lactic acid and glycolic acid and their respective saltsand derivatives; and beta-hydroxy acids, such as Salicylic acid(o-hydroxybenzoic acid) and its salts and pharmaceutically acceptablederivatives, which typically possess anti-inflammatory, as well askeratolytic, activity. Yet, another class of preferred keratolyticallyactive agents includes urea and its derivatives.

In one or more embodiments, the active agent is a retinoid. Retinoidsinclude, for example, retinol, retinal, all-trans retinoic acid andderivatives, isomers and analogs thereof. Etretinate, actiretin,isotretinoin, adapalene and tazarotene are further examples of saidretinoid isomers and analogs.

In one or more embodiments, the active agent is an insecticide or aninsect repellent agent.

In one or more embodiments, the active agent is an anti cancer agent.

In one or more embodiments, the active agent is a photodynamic therapy(PDT) agent. By way of example, such PDT agents can be modifiedporphyrins, chlorins, bacteriochlorins, phthalocyanines,naphthalocyanines, pheophorbides, purpurins, m-THPC, mono-L-aspartylchlorin e6, bacteriochlorins, phthalocyanines, benzoporphyrinderivatives, as well as photosensitizer precursors, such asaminolevulinic acid (ALA).

In one or more embodiments, the active agent is an agent useful in thetreatment of burns, wounds, cuts and ulcers. The foam compositions ofthe present invention may comprise a combination of anti-infectiveagents (against bacteria, fungi and/or viruses), anti-inflammatoryagents (steroidal and/or NSAIDs) and pain relieving components.

The foam compositions of the present invention, with or without furtheractive ingredients, are suitable for the further application as“cosmeceutical” preparation (cosmetic products with therapeuticbenefit), to treat “cosmetic” skin disorders, such as aging skin,wrinkles, hyperpigmentation (melasma, chloasma, freckles, etc.), scalyskin and other skin undesirable properties.

Any cosmetically active agent is considered an active agent in thecontext of the present invention. The CTFA Cosmetic Ingredient Handbookdescribes a wide variety of non-limiting cosmetic and pharmaceuticalingredients commonly used in the skin care industry, which are suitablefor use in the compositions of the present invention. Examples of theseingredient classes include: abrasives, absorbents, aesthetic componentssuch as fragrances, pigments, colorings/colorants, essential oils,astringents, etc. (e.g., clove oil, menthol, camphor, eucalyptus oil,eugenol, menthyl lactate, witch hazel distillate), anti-acne agents,anti-caking agents, antifoaming agents, anti-microbial agents (e.g.,iodopropyl butylcarbamate), antioxidants, binders, biological additives,buffering agents, bulking agents, chelating agents, chemical additives,colorants, cosmetic astringents, cosmetic biocides, denaturants, drugastringents, external analgesics, film formers or materials, e.g.,polymers, for aiding the film-forming properties and substantivity ofthe composition (e.g., copolymer of eicosene and vinyl pyrrolidone),opacifying agents, pH adjusters, propellants, reducing agents,sequestrants, skin bleaching and lightening agents (e.g., hydroquinone,kojic acid, ascorbic acid, magnesium ascorbyl phosphate, ascorbylglucosamine), skin-conditioning agents (e.g., humectants, includingmiscellaneous and occlusive), skin soothing and/or healing agents (e.g.,panthenol and derivatives (e.g., ethyl panthenol), aloe vera,pantothenic acid and its derivatives, allantoin, bisabolol, anddipotassium glycyrrhizinate), skin treating agents, and vitamins andderivatives thereof.

In one or more embodiments, the active agent is an agent useful in thetreatment of acne, wrinkles and scars. Examples of useful anti-acneactives include resorcinol, sulfur, salicylic acid and salicylates,alpha-hydroxy acids, nonsteroidal anti-inflammatory agents, benzoylperoxide, retinoic acid, isoretinoic acid and other retinoid compounds,adapalene, tazarotene, azelaic acid and azelaic acid derivatives,antibiotic agents, such as erythromycin and clyndamycin, zinc salts andcomplexes, and combinations thereof, in a therapeutically effectiveconcentration. Exemplary anti-wrinkle/anti-atrophy active agentssuitable for use in the compositions of the present invention includesulfur-containing D and L amino acids and their derivatives and salts,particularly the N-acetyl derivatives; thiols; hydroxy acids (e.g.,alpha-hydroxy acids such as lactic acid and glycolic acid and theirderivatives and salts; or beta-hydroxy acids such as salicylic acid andsalicylic acid salts and derivatives), urea, hyaluronic acid, phyticacid, lipoic acid; lysophosphatidic acid, skin peel agents (e.g.,phenol, resorcinol and the like), vitamin B3 compounds (e.g.,niacinamide, nicotinic acid and nicotinic acid salts and esters,including non-vasodilating esters of nicotinic acid (such as tocopherylnicotinate), nicotinyl amino acids, nicotinyl alcohol esters ofcarboxylic acids, nicotinic acid N-oxide and niacinamide N-oxide),vitamin B5 and retinoids (e.g., retinol, retinal, retinoic acid, retinylacetate, retinyl palmitate, retinyl ascorbate). In the case of dry,scaly skin (xerosis) and ichthyosis such agents can alleviate thesymptoms by temporary relief of itching associated with theseconditions.

In one or more embodiments, the active agent is an anti-oxidant or aradical scavenger. Anti-oxidants/radical scavengers such as ascorbicacid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbicacid derivatives (e.g., magnesium ascorbyl phosphate, sodium ascorbylphosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherolsorbate, tocopherol acetate, other esters of tocopherol, butylatedhydroxy benzoic acids and their salts,6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, gallic acid andits alkyl esters, especially propyl gallate, uric acid and its salts andalkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g.,N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g.,glutathione), dihydroxy fumaric acid and its salts, lycine pidolate,arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin,lysine, methionine, proline, superoxide dismutase, silymarin, teaextracts, grape skin/seed extracts, melanin, and rosemary extracts maybe used.

It is further pointed out that polyunsaturated fatty acids, containingomega-3 and omega-6 fatty acids (e.g., linoleic and linolenic acid,gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA)) are beneficial in the treatment of psoriasisand other skin inflammation conditions. Likewise, emollients andsilicone oils exert moisture-retaining and skin protective effects onthe skin. Thus, in a preferred embodiment, a skin protective foam isprovided, wherein the hydrophobic carrier comprises in full or in part,an organic liquid selected from the group consisting of emollients,silicone oil and oils rich in unsaturated fatty acids.

In one or more embodiments, the active agent is a self-tanning activeAgent, such as dihydroxyacetone.

According to another embodiment, the active agent comprises solid matteror particulate matter, i.e., material that is not soluble in the liquidcarrier composition of the foamable composition. For definitionpurposes, solid matter shall mean material that is not soluble in thefoamable composition more than 10% of the concentration intended to beincluded in said foamable composition. By way of example, the followingclasses of solid matter substances are presented: metallic oxides, suchas titanium dioxide, zinc oxide, zirconium oxide, iron oxide; siliconcontaining materials such as silicone oxide and talc; carbon, forexample in the form of amorphous carbon or graphite; insoluble oxidizingagents, such as benzoyl peroxide, calcium and magnesium hypochlorite;metallic Silver; cosmetic scrub materials, including, for example mealsof strawberry seeds, raspberry seeds, apricot seeds, sweet almond,cranberry seeds; and pigments.

According to certain embodiments, the active agent is selected from thegroup of solvent, surface active agent, foam adjuvant and gelling agent,which are, on a case-by-case basis, known to possess a therapeuticbenefit.

In one or more embodiments at least one or at least two active agentsare included in the composition.

Composition and Foam Physical Characteristics and Advantages

A pharmaceutical or cosmetic composition manufactured using the foamablecarrier of the present invention is very easy to use. When applied ontothe afflicted body surface of mammals, i.e., humans or animals, it is ina foam state, allowing free application without spillage. Upon furtherapplication of a mechanical force, e.g., by rubbing the composition ontothe body surface, it freely spreads on the surface and is rapidlyabsorbed.

The foamable composition can be in the state of (1) solutions; (2) areadily dispersable suspension; or (3) an emulsion. It is stable, havingan acceptable shelf life of a year, or at least two years at ambienttemperature, as revealed in accelerated stability tests. Polar solvents,hydrophobic carriers and propellants, which are a mixture of lowmolecular weight hydrocarbons, tend to impair the stability of emulsionsand to interfere with the formation of a stable foam upon release from apressurized container. It has been observed, however, that the foamablecompositions according to the present invention are surprisingly stable.Following accelerated stability studies, they demonstrate desirabletexture; they form fine bubble structures that do not break immediatelyupon contact with a surface, spread easily on the treated area andabsorb quickly.

The composition should also be free flowing, to allow it to flow throughthe aperture of the container, e.g., and aerosol container, and createan acceptable foam. Compositions containing semi-solid hydrophobicsolvents, e.g., white petrolatum, as the main ingredients of the oilphase of the emulsion, exhibit high viscosity and poor flowability andare inappropriate candidates for a foamable composition.

Foam quality can be graded as follows:

Grade E (excellent): very rich and creamy in appearance, does not showany bubble structure or shows a very fine (small) bubble structure; doesnot rapidly become dull; upon spreading on the skin, the foam retainsthe creaminess property and does not appear watery.

Grade G (good): rich and creamy in appearance, very small bubble size,“dulls” more rapidly than an excellent foam, retains creaminess uponspreading on the skin, and does not become watery.

Grade FG (fairly good): a moderate amount of creaminess noticeable,bubble structure is noticeable; upon spreading on the skin the productdulls rapidly and becomes somewhat lower in apparent viscosity.

Grade F (fair): very little creaminess noticeable, larger bubblestructure than a “fairly good” foam, upon spreading on the skin itbecomes thin in appearance and watery.

Grade P (poor): no creaminess noticeable, large bubble structure, andwhen spread on the skin it becomes very thin and watery in appearance.

Grade VP (very poor): dry foam, large very dull bubbles, difficult tospread on the skin.

Topically administrable foams are typically of quality grade E or G,when released from the aerosol container. Smaller bubbles are indicativeof more stable foam, which does not collapse spontaneously immediatelyupon discharge from the container. The finer foam structure looks andfeels smoother, thus increasing its usability and appeal.

As a further aspect of the foam is breakability. The breakable foam isthermally stable, yet breaks under sheer force. Sheer-force breakabilityof the foam is clearly advantageous over thermally induced breakability.Thermally sensitive foams immediately collapse upon exposure to skintemperature and, therefore, cannot be applied on the hand and afterwardsdelivered to the afflicted area.

The foam of the present invention has several advantages, when comparedwith hydroalcoholic foam compositions, such as described in U.S. Pat.Nos. 6,126,920 and 5,783,202:

-   -   (1) Breakability. The foam of the present invention is thermally        stable. Unlike hydroalcoholic foam compositions of the prior        art, the foam of the present invention is not “quick breaking”,        i.e., it does not readily collapse upon exposure to body        temperature environment. Sheer-force breakability of the foam is        clearly advantageous over thermally induced breakability, since        it allows comfortable application and well directed        administration to the target area.    -   (2) Skin drying and skin barrier function. Polar solvents known        to dry the skin and impair the integrity of the skin barrier. By        contrast, combining a polar solvent and a hydrophobic carrier,        as described herein, unwanted skin barrier damage is reduced, as        demonstrated in tran-epidermal water loss measurements.    -   (3) Irritability. Due to the improvement in skin barrier        function, skin irritability is corrected.

In terms of usability, the foamable composition is most advantageous, asrevealed by clinical trials:

(i) Ease of application.

-   -   When foam is released it expands and allows easy spreading on        the target area. This advantage is particularly meaningful in        regards to the treatment of large skin surfaces.    -   Upon application, the foam readily spreads and absorbs into the        skin.

(ii) The Foam is Drip-Free

-   -   The foam is not liquid and therefore does not leak when applied.    -   This allows precise application, without the product being        spread on clothes or other parts of the body.

Another property of the foam is specific gravity, as measured uponrelease from the aerosol can. Typically, foams have specific gravity ofless than 0.12 g/mL; or less than 0.12 g/mL; or less than 0.08 g/mL,depending on their composition and on the propellant concentration.

For the purpose of the specification the external limits of the variousranges given are approximate as will be appreciated by those skilled inthe art. Therefore, for the purpose of interpreting the outer limits ofthe range the limits shall be deemed to include up to a 20% leewayoutside the range, preferably a 10% leeway.

Fields of Applications

According to one or more embodiments of the present invention, thefoamable carrier and the foamable pharmaceutical or cosmetic compositionof the present invention are intended for administration to an animal ora human subject. In one or more embodiments, the composition is intendedto treat the skin, a body surface, a body cavity or a mucosal surface,e.g., the mucosa of the nose, mouth, eye, ear, respiratory system,vagina or rectum.

By including an appropriate active agent in the compositions of thepresent invention, the composition are useful in treating a patienthaving any one of a variety of dermatological disorders, which includeinflammation as one or their etiological factors (also termed“dermatoses”), such as classified in a non-limiting exemplary manneraccording to the following groups:

Dermatitis including contact dermatitis, atopic dermatitis, seborrheicdermatitis, nummular dermatitis, chronic dermatitis of the hands andfeet, generalized exfoliative dermatitis, stasis dermatitis; lichensimplex chronicus; diaper rash;

Bacterial infections including cellulitis, acute lymphangitis,lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneousinfections, staphylococcal scalded skin syndrome, folliculitis,furuncles, hidradenitis suppurativa, carbuncles, paronychial infections,and erythrasma;

Fungal Infections including dermatophyte infections, yeast Infections;parasitic Infections including scabies, pediculosis, creeping eruption;

Viral Infections;

Disorders of hair follicles and sebaceous glands including acne,rosacea, perioral dermatitis, hypertrichosis (hirsutism), alopecia,including male pattern baldness, alopecia areata, alopecia universalisand alopecia totalis; pseudofolliculitis barbae, keratinous cyst;

Scaling papular diseases including psoriasis, pityriasis rosea, lichenplanus, pityriasis rubra pilaris;

Benign tumors including moles, dysplastic nevi, skin tags, lipomas,angiomas, pyogenic granuloma, seborrheic keratoses, dermatofibroma,keratoacanthoma, keloid;

Malignant tumors including basal cell carcinoma, squamous cellcarcinoma, malignant melanoma, paget's disease of the nipples, kaposi'ssarcoma;

Reactions to sunlight, including sunburn, chronic effects of sunlight,photosensitivity;

Bullous diseases including pemphigus, bullous pemphigoid, dermatitisherpetiformis, linear immunoglobulin A disease;

Pigmentation disorders including hypopigmentation such as vitiligo,albinism and postinflammatory hypopigmentation and hyperpigmentationsuch as melasma (chloasma), drug-induced hyperpigmentation,postinflammatory hyperpigmentation;

Disorders of cornification including ichthyosis, keratosis pilaris,calluses and corns, actinic keratosis;

Pressure sores, open wounds, chronic wounds, open ulcers and burns;Disorders of sweating; and

Inflammatory reactions including drug eruptions, toxic epidermalnecrolysis, erythema multiforme, erythema nodosum, and granulomaannulare.

The same advantage is expected when the composition is topically appliedto a body cavity or mucosal surfaces, including, but not limited to thecranial cavity, the thoratic cavity, the abdominal cavity, the venteralcavity, the vagina, the rectum and penile cavities, the urinary tract,the nasal cavity, the mouth, the eye, the ear the peritoneum, the largeand small bowel, the caecum, bladder, and stomach, the cavity betweenthe uterus and the fallopian tubes, the ovaries and other body areas,which may accept topically-applied products. The composition of thepresent invention is suitable to treat conditions of a body cavity and amucosal membrane, such as post-surgical adhesions, chlamydia infection,gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus(HPV), genital warts, bacterial vaginosis, candidiasis, chancroid,granuloma Inguinale, lymphogranloma venereum, mucopurulent cervicitis(MPC), molluscum contagiosum, nongonococcal urethritis (NGU),trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeastinfection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN),contact dermatitis, pelvic inflammation, endometritis, salpingitis,oophoritis, genital cancer, cancer of the cervix, cancer of the vulva,cancer of the vagina, vaginal dryness, dyspareunia, anal and rectaldisease, anal abscess/fistula, anal cancer, anal fissure, anal warts,Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecalincontinence, constipation, polyps of the colon and rectum.

According to one or more embodiments of the present invention, thecompositions are also useful in the therapy of non-dermatologicaldisorders by providing transdermal or trans-mucosal delivery of anactive agent that is effective against non-dermatological disorders.

In one or more embodiments, the disorder is a health abnormality thatresponds to treatment with a hormone. A typical example of suchabnormality is sexual dysfunction in men and women whereby androgentherapy is successfully used to restore sexual function. Othernon-limiting examples of disorders/medical indications that are in thescope of treatment with a hormone according to the present invention areandrogen deficiency, estrogen deficiency, growth disorders,hypogonadism, cancer, vasomotor symptoms, menopausal disorders, vulvarand vaginal atrophy, urethritis, hypoestrogenism, osteoarthritis,osteoporosis, uterine bleeding, Hirsutism, Virilization, ovarian tumors,hypothalamic pituitary unit diseases, testicular tumors, prostatecancer, hypopituitarism, Klinefelter's syndrome, testicularfeminisation, orchitectomy, vasomotor symptoms (such as “hot flashes”)associated with the menopause, metabolic abnormalities and mooddisturbances.

The following examples further exemplify the, foamable carrier, thepharmaceutical and cosmetic compositions of the present invention,methods for preparing the same, and therapeutic uses of thecompositions. The examples are for the purposes of illustration only andare not intended to be limiting of the invention. Many variations may becarried out by one of ordinary skill in the art and are contemplatedwithin the full scope of the present invention.

A general procedure for preparing foamable compositions is set out in WO2004/037225 which is incorporated herin by reference. Moreover, withrespect to using one or more polar solvents, the polor solvent is addedto the aqueous phase mixture in the course of preparation.

Example 1—Foamable Carrier, Containing Polar Solvent (DimethylIsosorbide) and Hydrophobic Carrier (Caprylic/Capric Triglyceride)

Foam A Foam B Foam C % w/w % w/w % w/w Caprylic/capric 30.0 19.0 40.0triglyceride (Hydrophobic carrier) Dimethyl isosorbide 20.0 20.0 20.0(Polar solvent) Glyceryl oleate 1.0 2.0 1.0 (Surfactant) PPG-15 stearylether 5.0 15.0 5.0 (Surfactant) Lecithin (Surfactant) 20.0 20.0 10.0Sorbitan stearate — — 5.0 (Surfactant) Sucrose stearate 5.0 5.0 —(Surfactant) PVP K-90 0.5 0.5 0.5 (Polymeric agent) Preservative 0.5 0.50.5 Propane/Butane 8.00 8.00 8.00 (Propellant) Purified water to100.00to100.00 to100.00 Foam properties Foam quality Excellent ExcellentExcellent Density 0.06 0.08 0.06 Formulation type Dispersion HomogeneityHomogenious Homogenious Homogenious upon mild upon mild upon mildshaking shaking shaking

Example 2—Foamable Carrier, Containing Polar Solvent (DimethylIsosorbide and Propylene Glycol) and Hydrophobic Carrier(Caprylic/Capric Triglyceride and Isopropyl Myristate)

Foam D Foam E Foam F % w/w % w/w % w/w Caprylic/capric 5.00 5.00 5.00triglyceride (Hydrophobic carrier) Isopropyl myristate 5.00 5.00 5.00(Hydrophobic carrier) Dimethyl isosorbide 55.50  62.00  59.00  (Polarsolvent) Propylene glycol 2.50 — — (Polar solvent) Glyceryl monostearate— 1.00 1.00 (Surfactant) Sorbitan monostearate 8.00 5.00 8.00(Surfactant) Sucrose stearate 5.00 5.00 8.00 (Surfactant) Hydroxypropyl-— 0.50 — cellulose (Polymeric agent) Cetostearyl alcohol 8.00 8.00 —(Foam adjuvant) Stearyl alcohol — — 5.00 (Foam adjuvant) Oleyl alcohol2.50 — — (Foam adjuvant) Preservative 0.5  0.5  0.5  Propane/Butane 8.008.00 8.00 (Propellant) Purified water to100.00 to100.00 to100.00 Foamproperties Foam quality Excellent Excellent Good Density 0.13 0.23 0.21Formulation type Solution Solution Solution Homogeneity HomogeneousHomogeneous Homogeneous upon mild upon mild upon mild shaking shakingshaking

Example 3—Foamable Carrier, in the Form of Emulsion, Containing PolarSolvent (Diethyl Isosorbide) and Hydrophobic Carrier (Caprylic/CapricTriglyceride)

Foam G % w/w Caprylic/capric triglyceride (Hydrophobic carrier) 30.00Dimethyl isosorbide (Polar solvent) 20.00 Glyceryl monostearate(Surfactant) 2.00 PPG-15 stearyl ether 3.00 Sorbitan stearate(Surfactant) 2.00 Xanthan gum (Polymeric agent) 0.15 Hydroxypropylmethylcellulose (Polymeric agent) 0.15 Stearyl alcohol (Foam adjuvant)1.00 Preservative 0.5 Propane/Butane (Propellant) 8.00 Purified waterto100.00 Foam properties Foam quality Excellent Density 0.12 Formulationtype Emulsion Emulsion stability (centrifuge) Stable

Example 4—Foamable Carrier, in the Form of Emulsion, Containing PolarSolvent (Ethanol) and Hydrophobic Carrier (Caprylic/Capric Triglyceride)

Foam H Foam I % w/w % w/w Mineral oil (Hydrophobic carrier) 4.62 4.32Isopropyl myristate (Hydrophobic carrier) 4.62 4.32 Ethanol (Polarsolvent) 15.00  20.00  Glyceryl monostearate (Surfactant) 0.39 0.36Polysorbate 80 (Surfactant) 0.77 0.72 PEG-40 stearate (Surfactant) 2.312.16 Xanthan gum (Polymeric agent) 0.23 0.22 Hydroxypropylmethylcellulose (Polymeric agent) 0.23 0.22 Stearyl alcohol (Foamadjuvant) 0.77 0.72 Preservative 0.50 0.50 Propane/Butane (Propellant)8.00 8.00 Purified water to100.00 to100.00 Foam properties Foam qualityExcellent Excellent Density 0.04 0.04 Formulation type Emulsion EmulsionEmulsion stability (centrifuge) Stable Stable

Example 5—Non-Flammable Foamable Carriers

Foam J % w/w Caprylic/capric triglyceride (Hydrophobic carrier) 5.00Isopropyl myristate (Hydrophobic carrier) 5.00 Dimethyl isosorbide(Polar solvent) 59.00  Propylene glycol (Polar solvent) — Glycerylmonostearate (Surfactant) 1.00 Sorbitan monostearate (Surfactant) 8.00Sucrose stearate (Surfactant) 8.00 Hydroxypropylcellulose (Polymericagent) — Cetostearyl alcohol (Foam adjuvant) — Stearyl alcohol (Foamadjuvant) 5.00 Oleyl alcohol (Foam adjuvant) — Preservative 0.5  1,1,1,2tetrafluorethane (Dymel 134) 8.00 Purified water to100.00 Foam K % w/wMineral oil (Hydrophobic carrier) 4.32 Isopropyl myristate (Hydrophobiccarrier) 4.32 Ethanol (Polar solvent) 20.00 Glyceryl monostearate(Surfactant) 0.36 Polysorbate 80 (Surfactant) 0.72 PEG-40 stearate(Surfactant) 2.16 Xanthan gum (Polymeric agent) 0.22 Hydroxypropylmethylcellulose (Polymeric agent) 0.22 Stearyl alcohol (Foam adjuvant)0.72 Preservative 0.50 1,1,1,2 tetrafluorethane (Dymel 134) 8.00Purified water to100.00

Example 6—Inflammability Test

The following compositions were tested for inflammability according toEuropean Standard prEN 14851: (1) Foam F; (2) Foam I; (3) Foam J; and(4) Foam K.

Procedure: Approximately 5 g of foam, mousse gel or paste is sprayedfrom the aerosol container on to a watchglass. An ignition source (alighter) was placed at the base of the watchglass and any ignition andsustained combustion of the foam, mousse, gel or paste was observed. Thetest was carried out in a draught-free environment capable ofventilation, with the temperature controlled at 20° C.±5° C. andrelative humidity in the range of 30% to 80%. According to the standard,appearance of a stable flame which is at least 4 cm high and which ismaintained for at least 2 seconds defines a product as “inflammable”.

Results:

Foam F and Foam I were found “inflammable”.

Foam J and Foam K were found “non-flammable”.

Example 7

Exemplary concentrations of active agents in foamable compositions areset out in Table 2. Each active agent is added into, for example, any ofthe carriers listed in any of Examples 1 to 5 above in a therapeuticallyeffective concentration and amount. The methodology of addition is wellknown to those of the art. The composition is adjusted in each case sothat it is made up to 100% w/w as appropriate by purified water.

TABLE 2 Exemplary Concentrations of Examples of Active Agents Concen-Class tration Exemplary Use Hydrocortisone acetate 1% Steroid responsiveinflammation Betamethasone valerate 0.1%   and psoriasis or atopicdermatitis Clobetasol proprionate 0.05%   Acyclovir 5% Viral infection,herpes Ciclopirox 1% Fungal infection, seborrhea, dandruff, Clindomycin2% Bacterial infection, acne, rosacea, Azelaic acid 15%  Acne, rosacea,pigmentation disorder and various dermatoses Metronidazol 0.25%-2%Rosacea, bacterial infections and parasite infestations Diclofenac 1%Osteoarthritus, joint pain Tachrolimus 0.2%   Atopic dermatitis, eczemaand inflammation

The above examples represent different drug classes and it is to beunderstood that other drugs belonging to each of the classes representedabove may be included and used in the compositions of the presentinvention in a safe and effective amount.

1-52. (canceled)
 53. A foamable pharmaceutical composition comprising:(a) an emulsion comprising: (i) an organic carrier at a concentration of10% to 70% by weight of the composition, wherein the organic carriercomprises: a hydrophobic solvent comprising caprylic/caprictriglyceride, isopropyl myristate, and/or mineral oil; and a polarsolvent comprising dimethyl isosorbide and/or a short chain alcohol;(ii) a surfactant; (iii) a foam adjuvant at a concentration of about0.01% to about 5% by weight of the composition; (iv) a polymeric agentat a concentration of about 0.01% to about 5% by weight of thecomposition; and (v) water; (b) a liquefied or compressed gas propellantat a concentration of about 3% to about 25% by weight of thecomposition; and wherein the composition is provided in an aerosolcontainer and upon release from the container, the composition forms abreakable foam.
 54. The composition of claim 53, wherein the short chainalcohol comprises ethanol.
 55. The composition of claim 54, wherein thepolar solvent comprises ethanol at a concentration of about 15% to about20% by weight of the composition.
 56. The composition of claim 53,wherein the polar solvent comprises dimethyl isosorbide at aconcentration of about 20% by weight of the composition.
 57. Thecomposition of claim 53, wherein the hydrophobic solvent is at aconcentration of about 5% to about 30% by weight of the composition. 58.The composition of claim 53, wherein the emulsion further comprises anemollient.
 59. The composition of claim 53, wherein the emulsion furthercomprises a preservative.
 60. The composition of claim 53, wherein thesurfactant is at a concentration of about 0.1% to about 5% by weight ofthe composition.
 61. The composition of claim 53, wherein the surfactantcomprises a non-ionic surfactant and an ionic surfactant, and whereinthe ratio of the non-ionic surfactant to the ionic surfactant is greaterthan 6:1.
 62. The composition of claim 53, wherein the surfactant isselected from the group consisting of glyceryl monostearate, sorbitanstearate, polysorbate 80, PEG-40 stearate, and a mixture of two or morethereof.
 63. The composition of claim 53, wherein the foam adjuvant isat a concentration of about 0.01% to about 1% by weight of thecomposition.
 64. The composition of claim 53, wherein the foam adjuvantcomprises a fatty alcohol having 15 or more carbons in its carbon chain;a fatty acid having 16 or more carbons in its carbon chain; a fattyalcohol derived from beeswax; a mixture of alcohols, a majority of whichhas at least 20 carbon atoms in their carbon chain; a fatty alcoholhaving a double bond; a fatty acid having a double bond; a branchedfatty alcohol; a branched fatty acid; a fatty acid substituted with ahydroxyl group; and a mixture of two or more thereof.
 65. Thecomposition of claim 64, wherein the fatty alcohol having 16 or morecarbons in its carbon chain comprises stearyl alcohol.
 66. Thecomposition of claim 53, wherein the polymeric agent is selected from abioadhesive agent, a gelling agent, a film forming agent, and a phasechange agent.
 67. The composition of claim 53, wherein the polymericagent is selected from the group consisting of a locust bean gum, sodiumcaseinate, an egg albumin, a gelatin agar, a carrageenin gum, sodiumalginate, a xanthan gum, a quince seed extract, a tragacanth gum, a guargum, a starch, a chemically modified starch, a cellulose ether, an alkylcellulose, a hydroxyalkyl cellulose, a hydroxyethyl cellulose, ahydroxypropyl cellulose, a methyl cellulose, a carboxymethyl cellulose,a methylhydroxyethylcellulose, a methylhydroxypropylcellulose, ahydroxypropyl methylcellulose, a hydroxyethylcarboxymethylcellulose, acarboxymethylhydroxyethylcellulose, a hydroxypropyl guar gum, a solublestarch, a carboxyvinyl polymer, a polyvinylpyrrolidone, a polyvinylalcohol, a polyacrylic acid polymer, a polymethacrylic acid polymer, apolyvinyl acetate polymer, a polyvinyl chloride polymer, apolyvinylidene chloride polymer, an acrylic acid/ethyl acrylatecopolymer, a carboxyvinyl polymer, a silicone dioxide, apoly(acrylic)acid, a poly(methylvinyl ether/maleic anhydride) copolymer,a chitosan, an alginic acid, a hyaluronic acid, a pectin, a karaya gum,a cyclodextrin, a chemically modified cyclodextrin,hydroxypropyl-3-cyclodextrin, a poly(N-isopropylamide), a poloxamer, anda mixture of any two or more thereof.
 68. The composition of claim 53,wherein the liquefied or compressed gas propellant comprises propaneand/or butane.
 69. The composition of claim 53, wherein: (a) theemulsion comprises: (i) a hydrophobic solvent comprising caprylic/caprictriglyceride at a concentration of about 30% by weight of thecomposition; (ii) a polar solvent comprising dimethyl isosorbide at aconcentration of about 20% by weight of the composition; (iii) asurfactant comprising glyceryl monostearate and sorbitant stearate at acombined concentration of about 4% by weight of the composition; (iv) afoam adjuvant comprising stearyl alcohol at a concentration of about 1%by weight of the composition; (v) a polymeric agent comprising xanthangum and hydroxypropyl methylcellulose at a combined concentration ofabout 0.3% by weight of the composition; and (vi) water; (b) a liquefiedor compressed gas propellant comprising propane and butane at aconcentration of about 8% by weight of the composition.
 70. Thecomposition of claim 53, wherein: (a) the emulsion comprises: (i) ahydrophobic solvent comprising mineral oil and isopropyl myristate at acombined concentration of about 9.24% by weight of the composition; (ii)a polar solvent comprising ethanol at a concentration of about 15% byweight of the composition; (iii) a surfactant comprising glycerylmonostearate, polysorbate 80, and PEG-40 stearate at a combinedconcentration of about 3.37% by weight of the composition; (iv) a foamadjuvant comprising stearyl alcohol at a concentration of about 0.77% byweight of the composition; (v) a polymeric agent comprising xanthan gumand hydroxypropyl methylcellulose at a combined concentration of about0.46% by weight of the composition; and (vi) water; (b) a liquefied orcompressed gas propellant comprising propane and butane at aconcentration of about 8% by weight of the composition.
 71. Thecomposition of claim 53, wherein: (a) the emulsion comprises: (i) ahydrophobic solvent comprising mineral oil and isopropyl myristate at acombined concentration of about 8.64% by weight of the composition; (ii)a polar solvent comprising ethanol at a concentration of about 20% byweight of the composition; (iii) a surfactant comprising glycerylmonostearate, polysorbate 80, and PEG-40 stearate at a combinedconcentration of about 3.24% by weight of the composition; (iv) a foamadjuvant comprising stearyl alcohol at a concentration of about 0.72% byweight of the composition; (v) a polymeric agent comprising xanthan gumand hydroxypropyl methylcellulose at a combined concentration of about0.44% by weight of the composition; and (vi) water; (b) a liquefied orcompressed gas propellant comprising propane and butane at aconcentration of about 8% by weight of the composition.
 72. Thecomposition of claim 53, wherein the breakable foam has a density ofabout 0.04 g/mL to about 0.12 g/mL.
 73. The composition of claim 53,wherein the weight ratio between the polar solvent and the hydrophobicsolvent is between about 1:4 and about 4:1.
 74. The composition of claim53, wherein the emulsion further comprises an active agent.
 75. A methodof treating, alleviating, or preventing a disorder, comprising topicallyadministrating a breakable foam produced from the composition of claim74.
 76. The method of claim 75, wherein the disorder is asteroid-responsive inflammation, a viral infection, a fungal infection,a bacterial infection, a parasite infestation, a pigment disorder, adermatosis, psoriasis, atopic dermatitis, herpes, seborrhea, dandruff,acne, rosacea, osteoarthritis, a joint pain, or eczema.
 77. The methodof claim 75, wherein the active agent is hydrocortisone acetate,betamethasone valerate, clobetasol proprionate, acyclovir, ciclopirox,clindomycine, azelaic acid, metronidazole, diclofenac, or tachrolimus.